A New Constitutive Foxl2-Cre Mouse Model Reveals Foxl2-Derived Cell Fate in Reproductive and Non-Reproductive Tissues

Area of Science:

• Genetics and Developmental Biology
• Reproductive Medicine
• Human Disease Genetics

Background:

• FOXL2 is a crucial transcription factor for ovarian development and female fertility.
• Mutations in FOXL2 cause Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES), affecting eyelids and ovarian function.
• BPES presents with diverse phenotypes, including craniofacial, palate, and cardiac abnormalities.

Purpose of the Study:

• To generate and characterize a novel constitutive Foxl2-Cre mouse model for studying FOXL2 function.
• To map the developmental fate of cells expressing FOXL2 (Foxl2-derived cells) in various tissues.
• To investigate the role of FOXL2 in reproductive organ development and BPES-associated features.

Main Methods:

• CRISPR/Cas9 gene editing was used to create the Foxl2-Cre mouse model.
• Crossing Foxl2-Cre mice with Rosa-tdTomato reporter mice enabled permanent cell labeling.
• Detailed histological analysis was performed to identify Foxl2-derived cells in multiple organs.

Main Results:

• The Foxl2-Cre model demonstrated robust and specific labeling of FOXL2-expressing cells during fetal development.
• Foxl2-derived cells were identified in key reproductive tissues: fetal ovarian somatic cells (granulosa, interstitium, theca), anterior pituitary, uterus, and oviduct.
• Beyond reproductive organs, Foxl2-derived cells were found in the testis, external genitalia, head, palate, and heart outflow tract, relevant to BPES phenotypes.

Conclusions:

• The developed Foxl2-Cre mouse model is a valuable tool for studying reproductive organ development and function.
• The comprehensive mapping of Foxl2-derived cell fate provides new insights into the potential roles of FOXL2 in BPES.
• This research offers a new perspective on the etiology of the wide spectrum of clinical features associated with FOXL2 mutations.